Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients

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Genvigir, Fabiana D. V. ; Salgado, Patricia C. ; Felipe, Claudia R. ; Luo, Elena Y. F. ; Alves, Camila ; Cerda, Alvaro ; Tedesco-Silva, Jr., Helio ; Medina-Pestana, Jose O. ; Oliveira, Nagilla ; Rodrigues, Alice C. ; Doi, Sonia Q. ; Hirata, Mario H. ; Hirata, Rosario D. C.

• Document type: Journal article
• Source: PHARMACOGENETICS AND GENOMICS; v. 26, n. 10, p. 462-472, OCT 2016.
• Web of Science Citations: 17

Abstract

BackgroundPolymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.ObjectiveThe aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.Material and methodsBrazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.ResultsFrequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).ConclusionThe results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation. (AU)

• FAPESP's process: 11/10039-6 - Study of the expression and candidate gene polymorphisms of calcineurin inhibitors in renal transplant recipients
• Grantee: Rosario Dominguez Crespo Hirata
• Support Opportunities: Regular Research Grants